The CNS synthesizes and secretes several neuropeptides which attenuate the actions of morphine including CCK-8, Tyr-MIF, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (NPFF), alpha-MSH and dynorphin(1-17). The anti-opioid model of tolerance and dependence postulates that administration of morphine produces increased secretion of anti-opioids, which attenuate the effects of morphine, and thereby maintain a homeostatic balance. A prediction of the anti-opioid model is that administration of an anti-opioid should attenuate the development of tolerance and dependence. A major finding of this project is that administration of anti-NPFF IgG to dependent rats attenuates naloxone-induced withdrawal. In addition, recent autoradiographic studies have shown that the density of the opioid mu receptor in the brain is under tonic inhibitory control by NPFF. Importantly, the mu receptors in the mesolimbic system are regulated by NPFF. Preliminary studies indicate that NPFF antagonizes the reinforcing effects of morphine. Heroin addicts suffer from dysphoric mood states prior to and during their addiction, as well as during periods of abstinence. One hypothesis to explain this is increased levels of dynorphin, which, via activation of kappa opioid receptors, produces dysphoria. This hypothesis is being tested in the clinical protocol: Anti-opioid peptide levels in the plasma and CSF of drug abusers and age matched controls (IRP-192). We continue our collaborations with medicinal chemists to identify potent and selective kappa antagonists. The significance of this project to drug abuse reseIRPh is that the delineation of novel mechanisms involved in opioid tolerance and dependence will eventually lead to novel, and more specific treatments for addiction.